sepsis

It’s similar to the “precogs” who predict crime in the movie Minority Report, but for sepsis, the deadly response to infection. That’s how Tim Buchman, director of the Emory Critical Care Center, described an emerging effort to detect and ward off sepsis in ICU patients hours before it starts to make their vital signs go haywire.

As landmark clinical studies have documented, every hour of delay in giving someone with sepsis antibiotics increases their risk of mortality. So detecting sepsis as early as possible could save lives. Many hospitals have developed “sniffer” systems that monitor patients for sepsis risk. See our 2016 feature in Emory Medicine for more details.

What Shamim Nemati and his colleagues, including bioinformatics chair Gari Clifford, have been exploring is more sophisticated. A vastly simplified way to summarize it is: if someone has a disorderly heart rate and blood pressure, those changes can be an early indicator of sepsis.* It requires continuous monitoring – not just once an hour. But in the ICU, this can be done. The algorithm uses 65 indicators, such as respiration, temperature, and oxygen levels — not only heart rate and blood pressure. See below.

Example patient graph. Green = SOFA score. Purple = Artificial Intelligence Sepsis Expert (AISE) score. Red = official definition of sepsis. Blue = antibiotics. Black + red = cultures. Around 4 pm on December 20, roughly 8 hr prior to any change in the SOFA score, the AISE score starts to increase. The top contributing factors were slight changes in heart rate, respiration, and temperature, given that the patient had surgery in the past 12hr with a contaminated wound and was on a mechanical ventilator. Close to midnight on December 21, other factors show abnormal changes. Five hours later, the patient met the Sepsis-3 definition of sepsis.

As recently published in the journal Critical Care Medicine, Nemati’s algorithm can predict sepsis onset – with some false alarms – 4, 8 even 12 hours ahead of time. No predictor is going to be perfect, Nemati says. The paper lays out specificity, sensitivity and accuracy under various timelines. They get to an AUROC (area under receiving operating characteristic) performance of 0.83 to 0.85, which this explainer web site rates as good (B), and is better than any other previous sepsis predictor. Read more

Emory immunologists have identified a potential target for treatments aimed at reducing mortality in sepsis, an often deadly reaction to infection.

2B4 is an inhibitory molecule found on immune cells. You may have heard of PD1, which cancer immunotherapy drugs block in order to re-energize the immune system. 2B4 appears to be similar; it appears on exhausted T cells after chronic viral infection, and its absence can contribute to autoimmunity.

In their new paper in Journal of Immunology, Mandy Ford, Craig Coopersmith and colleagues show that 2B4 levels are increased on certain types of T cells (CD4+ memory cells) in human sepsis patients and in a mouse model of sepsis called CLP (cecal ligation + puncture). Genetically knocking out 2B4 or blocking it with an antibody both reduce mortality in the CLP model. The effect of the knockout is striking: 82 percent survival vs 13 percent for controls.

How does it work? When fighting sepsis, 2B4 knockout animals don’t have reduced bacterial levels, but they do seem to have CD4+ T cels that survive better. CD4+ T cells, especially memory cells, get killed in large numbers during sepsis, and this is thought to contribute to mortality. Read more

Are there more cases of a given disease because something is causing more, or because doctors have become more aware of that disease? A recent paper in JAMA tackles this question for sepsis, the often deadly response to infection that is the most expensive condition treated in US hospitals.

Researchers from several academic medical centers, including Emory, teamed up to analyze sepsis cases using two methods. The first is based on the ICD (International Classification of Diseases) codes recorded for the patient’s stay in the hospital, which the authors refer to as “claims-based.” The second mines electronic medical record (EHR) data, monitoring the procedures and tests physicians used when treating a patient. The first approach is easier, but might be affected by changing diagnosis and coding practices, while the second is not possible at every hospital.

“This project was undertaken by several large, high quality institutions that have the ability to well characterize their sepsis patients and connect their EHR data,” says Greg Martin, MD, who is a co-author of the JAMA paper along with David Murphy, MD, PhD. The lead author, Chanu Rhee, MD, MPH, is from Brigham and Women’s Hospital, and the entire project was part of a Prevention Epicenter program sponsored by the Centers for Disease Control and Prevention. Read more

Are you experienced? Your immune system undoubtedly is. Because of vaccinations and infections, we accumulate memory T cells, which embody the ability of the immune system to respond quickly and effectively to bacteria or viruses it has seen before.

Mandy Ford has teamed up with Craig Coopersmith to investigate sepsis, a relatively new field for her, and the collaboration has blossomed in several directions

“This is an issue we’ve been aware of in transplant immunology for a long time,” says Mandy Ford, scientific director of Emory Transplant Center. “Real life humans have more memory T cells than the mice that we usually study.”

In late-stage sepsis patients, dormant viruses that the immune system usually keeps under control, such as Epstein-Barr virus and cytomegalovirus, emerge from hiding. The situation looks a lot like that in kidney transplant patients, who are taking drugs to prevent immune rejection of their new organ, Ford says.

â€œSepsis is largely a face without a name in the EMS setting, â€œ Polito says. â€œThe goal of our study was to create a tool to assist EMS providers in naming this deadly condition at the point of first medical contact. Similar to other life-threatening, time-sensitive conditions like stroke and heart attack, naming sepsis is the first step in developing coordinated care pathways that focus on delivering rapid, life-saving treatment once the patient arrives at the hospital.â€

Whether dietary supplementation with vitamin D is beneficial, in terms of preventing disease, has been controversial. However, vitamin D has been reported to increaseÂ immune cellsâ€™ production of microbe-fighting proteins. That’s why Emory doctorsÂ have been testing whether high doses of vitamin D couldÂ be helpful for critical care patients, who need to ward off infections.

The results of a small-scale clinical trial, presented in Denver this week at the American Thoracic Society meeting, suggest thatÂ high doses of vitamin D could decrease the length of hospital stays in critically ill patients with respiratory failure. Read more

DNA usually occupies a privileged place inside the cell. Although cells in our body die all the time, an orderly process of disassembly (programmed cell death or apoptosis) generally keeps cellular DNA from leaking all over the place. DNA’s presence outside the cell means something is wrong: tissue injury has occurred and cells are undergoing necrosis.

Researchers from the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University have devised a way to exploit the properties of extracellular DNA to create an imaging agent for injured tissue. Niren Murthy and Mike Davis recently published a paper in Organic Letters describing the creation of â€œHoechst-IR.â€ This imaging agent essentially consists of the DNA-binding compound Hoechst 33258 (often used to stain cells before microscopy), attached to a dye that is visible in the near-infrared range. A water-loving polymer chain between the two keeps the new molecule from crossing cell membranes and binding DNA inside the cell.